The emergence of multi-drug resistant pathogens threatens to render currently used antibiotics ineffective in treating lung infections in cystic fibrosis (CF), the most common fatal genetic disease in the United States. Recently demonstrated difficulties with gene therapy strategies have moved that solution further into the future. The development of new antibiotics is therefore essential for CF patients. Peptidyl Membrane Interactive Molecules (Peptidyl MIMs(TM)) from Demeter BioTechnologies Ltd. are active against CF pathogens vitro, show low toxicity in primary cultures of human airway cells, and have a mechanism in of action that is likely different from that of traditional antibiotics. Our goals in phase I are to i) evaluate the cytotoxic activity of these peptides in vitro, ii) develop a Pseudomonas aeruginosa infection and test the efficacy of a Peptidyl MIMs(TM) in the mouse subcutaneous chamber model, and iii) screen newly designed Peptidyl MIMs(TM) for their activity against Burkholderia cepacia isolates from CF patients. Phase II will focus on defining the efficacy of Peptidyl MIMs(TM) in a CF mouse model and accomplishing short-term toxicity studies in two mammalian species. Our long term goal is to develop antibiotics for pulmonary application with low systemic and local toxicity for use in humans. PROPOSED COMMERCIAL APPLICATIONS: Cystic fibrosis (CF) is the most common fatal genetic disease in the United States and affects about 30,000 children and young adults. The median age of survival of a person with CF is about 30 years. The total cost of care of an adolescent with severe CF involving multiple hospitalizations over a 45-month period is approximately $396,000. (J Care Management 1996;5:173-181). The requirement for better therapies is therefore compelling for this multi-billion dollar life-threatening problem.